1. Field of the Invention
The invention relates to 2,8-disubstituted dibenzofurans, compositions containing the same and methods of using the same to antagonize the effects of leukotriene B.sub.4.
2. Description of the Prior Art
Leukotriene B.sub.4 (LTB.sub.4) is a product of the metabolism of arachidonic acid via the lipoxygenase pathway. It is produced by a number of inflammatory cell types including neutrophils, macrophages, mast cells and epithelial cells. The structure of LTB.sub.4 is as follows: ##STR1##
At the cellular level, release of LTB.sub.4 causes the aggregation and movement (chemokinesis and chemotaxis) of leukocytes, in particular neutrophils. Other biological actions of LTB.sub.4 on leukocyte function include release of lysozymal enzymes, expression of surface C3b receptors and enhancement of intraleukocyte cGMP levels. Further, it has been suggested that LTB.sub.4 may regulate lymphocytic elements of the immune response in vitro. Evidence for this is demonstrated by the respective inhibitory and stimulatory effects of LTB.sub.4 on the proliferation of helper-inducer and suppressor-cytotoxic T lymphocytes as well as by the modulation of monokine and lymphokine production.
The actions of LTB.sub.4 are mediated through the interaction of this molecule with specific receptors on the membranes of affected cells.
Systemically, LTB.sub.4 causes neutropenic effects when administered intravenously. At the cellular level, neutrophil accumulation is observed when LTB.sub.4 is infused intraocularly; neutrophil accumulation accompanied by plasma exudation is seen when injected intradermally in rabbits and man.
Due to its activity as a potent chemoattractant for leukocytes, LTB.sub.4 has been implicated in the pathogenesis of various inflammatory conditions including psoriasis, arthritis, gout, cystic fibrosis, inflammatory bowel disease and pulmonary microembolization syndromes. Indeed, it is possible to speculate upon the importance of LTB.sub.4 as a mediator in any condition characterized by an infiltration of white blood cells.
Antagonists of the interaction of LTB.sub.4 with its receptor would be used in the treatment of any of the previously mentioned inflammatory conditions as well as immune system disorders.